Method for preparation of aryl substituted alefinic secondary amino compounds

Abstract

Patients susceptible to or suffering from central nervous system are treated by administering an effective amount of an aryl substituted olefinic amine compound, such as (E)-metanicotine. (E)-metanicotine is provided from nicotine. Nicotine is reacted with ethyl chloroformate to produce ethyl N-methyl-N-[4-chloro-4-(3-pyridyl)butyl]carbamate, which then is reacted in the presence of potassium tert-butoxide, tetrahydrofuran and dimethylformamide to produce (E)-metanicotine N-ethyl carbamate, which then is subjected to hydrolysis using hydrochloric acid to produce a reaction mixture containing (E)-metanicotine. The reaction mixture containing (E)-metanicotine is adjusted to a slightly basic pH, and then contacted with dichloromethane. The resulting water immiscible phase then is separated from the aqueous phase. The aqueous phase, then is adjusted to a very basic pH, and then contacted with methyl tert-butyl ether. (E)-metanicotine is taken up by the methyl tert-butyl ether, and after separation of the methyl tert-butyl ether from the aqueous phase, the desired product is separated from the methyl tert-butyl ether.

What is claimed is: 
     
       1. A method for providing an aryl substituted olefinic secondary amine compound, the method comprising the steps of: a) subjecting a nicotinic compound having an aromatic functionality bonded to a cyclic functionality to conditions sufficient to open the cyclic functionality thereby providing a ring opened compound;   b) reacting the ring opened compound within an aprotic solvent and potassium tert-butoxide under conditions sufficient to produce an aryl substituted olefinic amine compound;   c) subjecting the aryl substituted olefinic amine compound so provided to contact with acid and conditions sufficient to provide an aryl substituted olefinic secondary amine within a reaction mixture;   d) adjusting the reaction mixture to a pH of about 8 to about 9, and then contacting that mixture with a water immiscible organic solvent, and then separating water immiscible phase from aqueous phase;   e) subjecting the aqueous phase to a pH above about 11, and then contacting that phase with a water immiscible organic solvent;   f) separating of water immiscible phase from aqueous phase, and collecting the water immiscible phase incorporating organic solvent and aryl substituted olefinic secondary amine compound; and   g) separating organic solvent from aryl substituted olefinic secondary amine compound.   
     
     
       2. The method of claim 1 whereby cause dehydrohalogenation of that compound, and thereby step a) is performed in the presence of ethylchloroformate, and step b) is performed to cause dehydrohalogenation of ring opened compound. 
     
     
       3. The method of claim 2 whereby in step d), the pH of the mixture is adjusted to 8.2-8.3. 
     
     
       4. The method of claim 1 whereby step a) and step b) each are carried out at a temperature below 35° C. and 75° C., respectively. 
     
     
       5. The method of claim 1 whereby the nicotinic compound of step a) is nicotine and the aryl substituted olefinic secondary amine compound is (E)-metanicotine. 
     
     
       6. The method of claim 1 whereby the aprotic solvent of step b) includes tetrahydrofuran. 
     
     
       7. The method of claim 6 whereby the aprotic solvent of step b) includes dimethylformamide. 
     
     
       8. The method of claim 1, wherein the nicotinic compound is nicotine and the aryl substituted olefinic secondary amine compound is 5-bromometanicotine.